Unusual Changes in the U.S. Treasury Security Market During the Fourth Round of Quantitative Easing

The Covid-19 Pandemic and policy response rattled the US Treasury markets. Conventional US Treasuries, inflation adjusted US Treasuries, and the relationship between the two developed in ways such that ignoring changes in real interest rates yielded distorted inflation expectations estimates. Since the beginning of the pandemic, monetary policy kept nominal rates low and close to zero, but positive. Real rates, on the other hand, became increasingly negative. The relationship between the two market rates became negatively correlated, and distorted because of the fourth round of quantitative easing, along with the Fed preventing nominal yields from turning negative. Federal Reserve actions during the Covid-19 pandemic drove a larger wedge between nominal interest rates and real interest rates in the inflation adjusted market

Optimized media and workflow for the expansion of human pluripotent stem cells as aggregates in suspension cultures

3D suspension culture enables scale-up of human pluripotent stem cell (hPSC) manufacturing. However, media and methods optimized for 2D adherent cultures can lead to low volumetric productivity and laborious workflow in suspension cultures. To overcome these limitations we developed fed-batch media based on either mTeSRTM1 (BSA-containing) or TeSRTM-E8TM (animal component-free) for hPSC expansion as aggregates in suspension cultures. Fed-batch feeding protocols are more efficient and cost-effective than batch media changes because only exhausted components are replenished. Optimization studies were performed using human embryonic (H7 and H9), and human induced pluripotent (WLS-1C and STiPS-M001) stem cell lines. Suspension cultures were fed daily using either 50% medium exchanges of standard 2D media, or fed-batch optimized media and protocols. hPSC aggregate diameter must be kept below 350 μm to maintain cell viability and phenotype. With observed growth rates, aggregates required passaging every 3 or 4 days into clumps of 5-10 cells with Gentle Cell Dissociation Reagent. Clumps were re-seeded into fresh test medium plus 10 μM Y-27632. Passaging and feeding cycles were repeated for at least 5 passages. Optimization was performed by iteratively modifying the feed solution to maintain consistent nutrient levels and maximal growth rate while maintaining cell quality. Control and optimized fed-batch formulations demonstrated between 1.4 and 1.8-fold expansion per day, \u3e90% viability, Oct4 and TRA-1-60 expression \u3e90%, in vitro trilineage differentiation, and normal karyotype (n=8 independent cultures). Suspension culture optimized mTeSRTM-3D or TeSRTM-E8TM3D fed-batch media enables the cost-effective production of hPSCs as aggregates with efficient workflow and high cell quality

Optimized media and workflow for the expansion of human pluripotent stem cells as aggregates in suspension

3D suspension culture enables the efficient and cost-effective scale-up of human pluripotent stem cell (hPSCs) manufacturing. However, media optimized for 2D adherent cultures can lead to low volumetric productivity and inefficient workflow. To overcome these limitations we developed mTeSRTM3D, a defined medium based on mTeSRTM1, and novel protocols for fed-batch culture of hPSC aggregates. Human embryonic stem cell (hESC) lines (H1 or H9) or human induced pluripotent stem cell (hiPSC) lines (WLS-1C or STiPS-M001) that were previously maintained in 2D mTeSRTM1 culture were seeded into multiple suspension culture vessels containing mTeSRTM3D Seed Medium plus 10 μM Y-27632 ROCK inhibitor. 3D cultures were maintained using either daily 50% mTeSRTM1 medium exchanges (control) or using a fed-batch protocol whereby the culture medium was supplemented daily with mTeSRTM3D Feed Medium. After 3 or 4 days in suspension culture, aggregates were harvested, dissociated into small clumps with Gentle Cell Dissociation Reagent (GCDR) or single cell suspensions enzymatically, and re-seeded in mTeSRTM3D Seed Medium plus 10 μM Y-27632. Passaging and feeding cycles were repeated for at least 5 passages. 3D cultures were assessed for growth, viability, hPSC marker expression, in vitro differentiation potential, and karyotype. In addition, media was analyzed for molar glucose to lactate yield to characterize metabolism. By day 4, aggregates cultured in mTeSRTM3D typically grew to a mean diameter of 350 μm, with a 5-fold increase in cell number. Using mTeSRTM3D up to 109 cells can be produced from a single plate within 2-3 weeks representing a greater than 500-fold expansion. hPSC cultures maintained in mTeSRTM3D differentiated into all 3 germ layers with high efficiency. The average volumetric productivities were 0.7, 3.1 and 6.9 (x105) viable cells / mL in 2D, daily 50% media exchange, and mTeSRTM3D cultures, respectively. Using the GCDR clump passaging protocol, mTeSRTM3D cultured hPSCs retained normal karyotypes. Culture performance was evaluated in shaker bottles, spinner flasks and bioreactors. Performance in each culture system was comparable confirming straightforward scale-up and wide applicability. Typical growth rates were on the order of 1.5-fold expansion per day. Metabolic activity as assessed by the moles lactate produced to glucose consumed was 1.7, consistent with a primarily glycolytic metabolism. Image analysis was performed to estimate aggregate size during growth. Adaptation times for cells moving from 2D to 3D aggregate culture varied with different cell lines; typically one passage in 3D was required before consistent expansion passage over passage was obtained. Additionally, protocols were developed for use on a Hamilton® robotic platform for reproducible, matrix-free, high-throughput hPSC suspension culture at a small scale. mTeSRTM3D enables efficient scale-up and scale-down of hPSC cultures with greatly simplified workflow

Adaptation of a Vocabulary Test from British Sign Language to American Sign Language

This study describes the adaptation process of a vocabulary knowledge test for British Sign Language (BSL) into American Sign Language (ASL) and presents results from the first round of pilot testing with twenty deaf native ASL signers. The web-based test assesses the strength of deaf children’s vocabulary knowledge by means of different mappings of phonological form and meaning of signs. The adaptation from BSL to ASL involved nine stages, which included forming a panel of deaf/hearing experts, developing a set of new items and revising/replacing items considered ineffective, and piloting the new version. Results provide new evidence in support of the use of this methodology for assessing sign language, making a useful contribution toward the availability of tests to assess deaf children’s signed language skills

Determination of the Cosmic Distance Scale from Sunyaev-Zel'dovich Effect and Chandra X-ray Measurements of High Redshift Galaxy Clusters

We determine the distance to 38 clusters of galaxies in the redshift range 0.14 < z < 0.89 using X-ray data from Chandra and Sunyaev-Zeldovich Effect data from the Owens Valley Radio Observatory and the Berkeley-Illinois-Maryland Association interferometric arrays. The cluster plasma and dark matter distributions are analyzed using a hydrostatic equilibrium model that accounts for radial variations in density, temperature and abundance, and the statistical and systematic errors of this method are quantified. The analysis is performed via a Markov chain Monte Carlo technique that provides simultaneous estimation of all model parameters. We measure a Hubble constant of 76.9 +3.9-3.4 +10.0-8.0 km/s/Mpc (statistical followed by systematic uncertainty at 68% confidence) for an Omega_M=0.3, Omega_Lambda=0.7 cosmology. We also analyze the data using an isothermal beta model that does not invoke the hydrostatic equilibrium assumption, and find H_0=73.7 +4.6-3.8 +9.5-7.6 km/s/Mpc; to avoid effects from cool cores in clusters, we repeated this analysis excluding the central 100 kpc from the X-ray data, and find H_0=77.6 +4.8-4.3 +10.1-8.2 km/s/Mpc. The consistency between the models illustrates the relative insensitivity of SZE/X-ray determinations of H_0 to the details of the cluster model. Our determination of the Hubble parameter in the distant universe agrees with the recent measurement from the Hubble Space Telescope key project that probes the nearby universe.Comment: ApJ submitted (revised version

X-ray and Sunyaev-Zel'dovich Effect Measurements of the Gas Mass Fraction in Galaxy Clusters

We present gas mass fractions of 38 massive galaxy clusters spanning redshifts from 0.14 to 0.89, derived from Chandra X-ray data and OVRO/BIMA interferometric Sunyaev-Zel'dovich Effect measurements. We use three models for the gas distribution: (1) an isothermal beta-model fit jointly to the X-ray data at radii beyond 100 kpc and to all of the SZE data,(2) a non-isothermal double beta-model fit jointly to all of the X-ray and SZE data, and (3) an isothermal beta-model fit only to the SZE spatial data. We show that the simple isothermal model well characterizes the intracluster medium (ICM) outside of the cluster core in clusters with a wide range of morphological properties. The X-ray and SZE determinations of mean gas mass fractions for the 100 kpc-cut isothermal beta-model are fgas(X-ray)=0.110 +0.003-0.003 +0.006-0.018 and fgas(SZE)=0.116 +0.005-0.005 +0.009-0.026, where uncertainties are statistical followed by systematic at 68% confidence. For the non-isothermal double beta-model, fgas(X-ray)=0.119 +0.003-0.003 +0.007-0.014 and fgas(SZE)=0.121 +0.005-0.005 +0.009-0.016. For the SZE-only model, fgas(SZE)=0.120 +0.009-0.009 +0.009-0.027. Our results indicate that the ratio of the gas mass fraction within r2500 to the cosmic baryon fraction is 0.68 +0.10-0.16 where the range includes statistical and systematic uncertainties. By assuming that cluster gas mass fractions are independent of redshift, we find that the results are in agreement with standard LambdaCDM cosmology and are inconsistent with a flat matter dominated universe.Comment: ApJ, submitted. 47 pages, 5 figures, 8 table

Exploring the Potential Antidepressant Mechanisms of TNFα Antagonists

Human and animal studies suggest an intriguing relationship between the immune system and the development of depression. Some peripherally produced cytokines, such as TNF-α, can cross the blood brain barrier and result in activation of brain microglia which produces additional TNF-α and fosters a cascade of events including decreases in markers of synaptic plasticity and increases in neurodegenerative events. This is exemplified by preclinical studies, which show that peripheral administration of pro-inflammatory cytokines can elicit depression-like behavior. Importantly, this depression-like behavior can be ameliorated by anti-cytokine therapies. Work in our laboratory suggests that TNF-α is particularly important for the development of a depressive phenotype and that TNF-α antagonists might have promise as novel antidepressant drugs. Future research should examine rates of inflammation at baseline in depressed patients and whether anti-inflammatory agents could be included as part of the treatment regimen for depressive disorders

Report on the Third Workshop on Sustainable Software for Science: Practice and Experiences (WSSSPE3)

This report records and discusses the Third Workshop on Sustainable Software for Science: Practice and Experiences (WSSSPE3). The report includes a description of the keynote presentation of the workshop, which served as an overview of sustainable scientific software. It also summarizes a set of lightning talks in which speakers highlighted to-the-point lessons and challenges pertaining to sustaining scientific software. The final and main contribution of the report is a summary of the discussions, future steps, and future organization for a set of self-organized working groups on topics including developing pathways to funding scientific software; constructing useful common metrics for crediting software stakeholders; identifying principles for sustainable software engineering design; reaching out to research software organizations around the world; and building communities for software sustainability. For each group, we include a point of contact and a landing page that can be used by those who want to join that group's future activities. The main challenge left by the workshop is to see if the groups will execute these activities that they have scheduled, and how the WSSSPE community can encourage this to happen

Photoreversible interconversion of a phytochrome photosensory module in the crystalline state.

A major barrier to defining the structural intermediates that arise during the reversible photointerconversion of phytochromes between their biologically inactive and active states has been the lack of crystals that faithfully undergo this transition within the crystal lattice. Here, we describe a crystalline form of the cyclic GMP phosphodiesterases/adenylyl cyclase/FhlA (GAF) domain from the cyanobacteriochrome PixJ in Thermosynechococcus elongatus assembled with phycocyanobilin that permits reversible photoconversion between the blue light-absorbing Pb and green light-absorbing Pg states, as well as thermal reversion of Pg back to Pb. The X-ray crystallographic structure of Pb matches previous models, including autocatalytic conversion of phycocyanobilin to phycoviolobilin upon binding and its tandem thioether linkage to the GAF domain. Cryocrystallography at 150 K, which compared diffraction data from a single crystal as Pb or after irradiation with blue light, detected photoconversion product(s) based on Fobs - Fobs difference maps that were consistent with rotation of the bonds connecting pyrrole rings C and D. Further spectroscopic analyses showed that phycoviolobilin is susceptible to X-ray radiation damage, especially as Pg, during single-crystal X-ray diffraction analyses, which could complicate fine mapping of the various intermediate states. Fortunately, we found that PixJ crystals are amenable to serial femtosecond crystallography (SFX) analyses using X-ray free-electron lasers (XFELs). As proof of principle, we solved by room temperature SFX the GAF domain structure of Pb to 1.55-Å resolution, which was strongly congruent with synchrotron-based models. Analysis of these crystals by SFX should now enable structural characterization of the early events that drive phytochrome photoconversion